Protection of the kidney after temporary ischemia: free radical scavengers

Free radicals have been implicated in the damage caused by tissue ischemia and reperfusion. Canine kidneys were subjected to a 60-minute period of normothermic ischemia. One group of animals received intra-arterial superoxide dismutase (SOD, 17.6 mg/50 ml, 50,000 units) at the end of the ischemic period, whereas a second group received albumin (17.6 mg/50 ml). The kidneys treated with SOD demonstrated significantly less edema formation (1.0 +/- 0.3% wet weight vs. 1.8 +/- 0.2%, mean +/- SEM, p less than 0.05) and lower renovascular resistance (44.0 +/- 5.6 dynes-sec/cm5 vs. 64.0 +/- 12.0, p less than 0.05). The SOD group displayed greater preservation of both glomerular filtration rate (45.9 +/- 6.1% of baseline vs. 23.7 +/- 5.8%, p less than 0.05) and urine flow (1.3 +/- 0.4 ml/min vs. 0.3 +/- 0.1, p less than 0.05). We conclude that the free radical scavenger SOD provides significant protection of the kidney during ischemia and reperfusion.     

Use of oxygen radical scavengers on autografted pig kidneys after warm ischemia and 48-hour perfusion preservation

Oxygen free radicals generated during the reperfusion of an ischemic organ may cause further cellular injury; removal of these oxygen radicals by scavengers protects tissue from reperfusion injury. Thus, oxygen radical scavengers could protect kidneys after warm ischemia and long hypothermic perfusion. Porcine kidneys were incubated at 37 degrees C for 45 minutes, placed on a pulsatile perfusion apparatus at 7 degrees C for 48 hours, and then autografted to iliac vessels. Superoxide dismutase (10 mg) and catalase (10 mg) in 10 mL of phosphate-buffered saline solution were infused into the renal artery during a three-minute interval before reperfusion. The kidneys treated with the superoxide dismutase-catalase solution had significantly improved function compared with controls receiving only phosphate-buffered saline solution. The mean (+/- SEM) serum creatinine level on postoperative day 5 was 510 +/- 100 mumol/L (5.75 +/- 1.12 mg/dL) (n = 12) vs the control value of 840 +/- 90 mumol/L (9.54 +/- 1.01 mg/dL) (n = 11). There was more extensive cellular damage in the control kidneys. This demonstrates the efficacy of oxygen radical scavengers in protecting pig kidneys after warm ischemia and prolonged preservation.     

Pentoxifylline in the isolated perfused rat kidney

The effects of pentoxifylline, a new methylxanthine with marked hemorrheologic properties, were studied following brief renal artery occlusion in the isolated rat kidney model perfused with cell-free Krebs-Henseleit buffer. Anuria was observed in 3 of 6 control kidneys within 5 min after reperfusion; urine flow was maintained in all rat kidneys perfused with pentoxifylline (2500 ng/ml). Glomerular filtration rate was significantly greater in kidneys administered pentoxifylline compared with controls following 40 min of postocclusion reperfusion (460 +/- 100 vs. 100 +/- 110 microliters/min/gKW; P less than 0.01). Pretreatment of kidneys with indomethacin, a nonspecific cyclooxygenase inhibitor, blocked the protective effects of pentoxifylline in this setting. These data suggest that the addition of pentoxifylline may prevent hypoxia-related changes in renal function of transplanted kidneys. Stimulation of renal prostaglandin synthesis, as well as an interaction at the level of the adenosine receptors, were most likely responsible for the observed beneficial effects of pentoxifylline.     

Inhibition of thromboxane (Tx) synthesis by free radical scavengers

Treatment with thromboxane (Tx) synthase inhibitors or free radical scavengers has been shown to afford protection from renal ischemia. Since free radicals are closely associated with thromboxane (Tx) synthesis, this study examines the thesis that free radical scavengers inhibit formation of Tx. Anesthetized rats (n = 42) underwent right nephrectomy. By random choice, before 45 min of left renal pedicle clamping, rats received: 0.5 ml dextrose placebo IV (n = 6); the hydroxyl radical scavenger dimethyl-thiourea (DMTU), 500 mg/kg IV (n = 10); or the superoxide scavenger superoxide dismutase (SOD), 24,000 Sigma Units (SU)/kg IV (n = 12). This dose of SOD was repeated before release of the clamp. Treatment with DMTU and SOD decreased plasma TxB2 levels following 5 min of reperfusion from 2,480 pg/ml in dextrose treated controls to 1,155 pg/ml (p less than 0.01) and 1,419 pg/ml (p less than 0.03), respectively. At 24 hr, DMTU and SOD therapy decreased creatinine from 3.0 mg/dl in controls to 1.6 mg/dl (p less than 0.01) and 2.1 mg/dl (p less than 0.05), respectively. At 24 hr, DMTU but not SOD decreased left renal weight from 113 to 94% (p less than 0.0003) of the weight of the previously removed right kidney, and histologically prevented acute tubular necrosis (p less than 0.05). In nephrectomized but nonischemic sham control rats (n = 7) plasma TxB2 and 6-keto-PGF1 alpha concentrations were 757 pg/ml and 82 pg/ml, creatinine level 0.9 mg/dl and kidney weight 94% of the previously removed right kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney

BACKGROUND: CO-releasing molecule-3 (CORM-3) is a transitional metal carbonyl that liberates carbon monoxide under appropriate conditions. Carbon monoxide exerts effects on intracellular apoptotic and inflammatory pathways, which suggest a role in reducing the effects of renal ischemia/reperfusion (I/R) injury. This study investigated the effects of CORM-3 administered at the time of reperfusion in a model of controlled nonheartbeating donor kidneys. METHODS: Porcine kidneys (n=4) were subjected to 10 min warm ischemia and 18 hr cold storage (CS) and then treated as follows: CORM-3 (50, 100, 200, and 400 microM doses), iCORM-3 (inactive carbon monoxide-releasing molecule, 50 microM), and control (no further intervention). Renal hemodynamics and function were then measured during 3-hr reperfusion with autologous blood using an isolated organ-perfusion system. RESULTS: CORM-3 at a concentration of 50 microM improved renal blood flow (RBF) compared with the iCORM and control groups (area under the curve 774+/-19 vs. 448+/-88 vs. 325+/-70, respectively, P=0.002). CO-releasing molecule-3 at a concentration of 50 microM also improved renal function during reperfusion with a greater area under the curve for creatinine clearance (CORM-3: 14+/-6 vs. iCORM: 3.3+/-0.1 vs. control: 2.2+/-2 mL/min, P=0.006) and higher urine output (CORM-3: 793+/-212 vs. iCORM: 368+/-72 vs. control: 302+/-211 mL, P=0.01). CO-releasing molecule-3 at a concentration of 100 microM exerted similar effects. Treatment with CORM-3 at higher doses (200 and 400 microM) led to poor renal hemodynamics and function after reperfusion. CONCLUSION: Low-dose CORM-3 significantly ameliorates the effects of ischemia/reperfusion in a porcine model of controlled nonheartbeating donor kidney transplantation.     

Ezetimibe treatment in hypercholesterolemic kidney transplant patients is safe and effective and reduces the decline of renal allograft function: a pilot study.

BACKGROUND: Ezetimibe has shown efficacy in the therapy of hypercholesterolemia in renal transplant patients. This is the first study investigating the effect of ezetimibe on renal function in kidney transplant recipients. METHODS: Fifty-six patients with statin-resistant hypercholesterolemia (total cholesterol >200 mg/dl) after renal transplantation received additional ezetimibe therapy (10 mg/day) for 12 months. A group receiving statin therapy (n=28) served as controls in this prospective study. RESULTS: Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibe-treated patients but remained stable in the control group (delta total cholesterol: -24+/-49 mg/dl vs 19+/-49 mg/dl, P<0.01; delta LDL: -30+/-39 mg/dl vs -3+/-31 mg/dl, P<0.01). Mean creatinine clearance remained stable in ezetimibe-treated patients but decreased significantly in control group (delta Cockcroft-Gault: 0.9+/-7.3 ml/min vs - 4.8+/-12.8 ml/min, P=0.025; delta Modification of Diet in Renal Disease: -0.4+/-6.2 ml/min/1.73 m(2) vs 4.7+/-8.8 ml/min/1.73 m(2), P=0.033). CONCLUSIONS: The data of our prospective case-control study suggest that ezetimibe appears to ameliorate the decline of renal function after renal transplantation.     

Renal kallikrein and hemodynamic abnormalities of diabetic kidney.

The relationship between renal hemodynamic abnormalities and renal kallikrein activity was studied in streptozocin-induced diabetic rats. Diabetic rats were either not treated with insulin and had plasma glucose levels greater than 400 mg/dl (severely hyperglycemic diabetic [SD]) or were treated with 1.5-1.75 U/day protamine zinc insulin and had glucose levels of 200-300 mg/dl (moderately hyperglycemic diabetic [MD]). In SD rats, kidney tissue level and excretion of active kallikrein were reduced after 3 wk compared with age-matched nondiabetic control rats (tissue, 11.7 +/- 1.9 vs. 20.5 +/- 1.8 ng/mg protein, P less than 0.005; urine, 126 +/- 12 vs. 179 +/- 10 micrograms/24 h, P less than 0.005). Despite increased kidney size, renal plasma flow (RPF) was reduced in SD rats (5.38 +/- 0.23 vs. 6.37 +/- 0.20 ml/min, P less than 0.05). Glomerular filtration rate (GFR) was not significantly lower (2.77 +/- 0.60 vs. 3.02 +/- 0.56 ml/min). In MD rats, kidney tissue level and excretion of active kallikrein were increased after 5 wk compared with age-matched nondiabetic control rats (tissue, 28.4 +/- 1.3 vs. 23.3 +/- 1.7 ng/mg protein, P less than 0.05; urine, 289 +/- 16 vs. 196 +/- 13 micrograms/24 h, P less than 0.001). In MD rats, GFR and RPF were increased (3.80 +/- 0.11 and 8.04 +/- 0.17 ml/min, respectively) compared with control rats (3.22 +/- 0.05 and 7.28 +/- 0.09 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction of renal reperfusion damage following warm ischemia by allopurinol and superoxide dismutase

Preserved organs are damaged not only by the ischemic injury due to lack of oxygen. The reperfusion injury mediated by oxygen free radicals is an important factor in the postischemic organ failure. The prevention of free radical-induced reperfusion injury with allopurinol (AP) and superoxide dismutase (SOD) is shown in a warm ischemia kidney model. Rats were treated with allopurinol (40 mg/kg i.v.) one hour, or with SOD (20,000 IU/kg i.v.) one minute before reperfusion after a period of 35 minutes of warm ischemia. Allopurinol and SOD reduced significantly the postischemic kidney failure with a less important increase of creatinine. Creatinine levels on day three in the control group: 517 +/- 87 mumol/ml, in the SOD-group: 206 +/- 105 mumol/ml, and in the AP-group: 163 +/- 81 mumol/ml (anal. of variance: p = 0.0001). AP has a wide therapeutic range. We feel, that it is important to confirm the prevention of reperfusion injury by allopurinol prophylaxis clinically.     

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

8-Br-cyclic GMP given during reperfusion improves post-transplant lung edema and free radical injury.

Substitution of the NO-pathway reduces ischemia/reperfusion injury following lung transplantation. 8-Br-cGMP is a membrane permeable analogue of cGMP, the second messenger of NO. In this study the effect of continuous administration of 8-Br-cGMP on early graft function was evaluated. METHODS: Unilateral left lung transplantation was performed in 10 weight-matched pigs (23-30 kg). Donor lungs were flushed with 1.51 cold (1 degree C) LPD solution and preserved for 20 hours. In Group I (n = 5), 8-Br-cGMP (0.2 mg/kg/h) was given continuously over the entire observation time starting 15 min before reperfusion. Group II served as control, no 8-Br-cGMP was administered. In both groups, 250 microg PGE1 was injected into the pulmonary artery (PA) before flush. One hour after reperfusion the recipients contralateral right PA and bronchus were ligated to assess isolated graft function only. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, mean systemic arterial pressure and gas exchange were assessed during a 5-hour observation period. Lipid peroxidation as indicator for free radical mediated injury and neutrophil migration to the allograft were measured at the end of the assessment. RESULTS: EVLWI was significantly reduced in animals treated with 8-Br-cGMP (overall difference P = 0.024) with a peak 2 hours after reperfusion (Group I, 8.2+/-0.3 mg/ml vs Group II, 10.1+/-0.6 mg/ml; P = 0.039). Also in Group I the free radical mediated tissue injury was significantly lower when compared to Group II (Group I, 61.8+/-12.3 pmol/g vs Group II, 120.7+/-7.2 pmol/g; P = 0.006). A tendency towards a reduced neutrophil migration after 8-Br-cGMP infusion was shown; however, the changes in comparison to the control animals were not statistically significant (Group I, 1.0+/-0.2 deltaOD/mg/min vs Group II, 1.7+/-0.3 deltaOD/mg/min; P = 0.13). Pulmonary- and systemic hemodynamics, and allograft gas exchange did not differ between groups. CONCLUSIONS: The results indicate that substitution of the NO pathway by administration of the second messenger cGMP at the time of reperfusion improves post-transplant lung allograft function.     

Role of iron in postischemic renal injury in the rat

To determine whether iron participates in free radical-mediated postischemic renal injury and lipid peroxidation, we examined the effects of removal of endogenous iron or provision of exogenous iron following renal ischemia, as well as the effects of renal ischemia and reperfusion on renal venous and urinary "free" iron. Rats underwent 60 minutes of renal ischemia and were studied after either 24 hours (inulin clearance) or 15 minutes (renal malondialdehyde content) of reperfusion. Infusion of the iron chelator deferoxamine (200 mg/kg/hr) during the first 60 minutes of reperfusion resulted in a marked improvement in renal function (inulin clearance: 879 +/- 154 vs. 314 +/- 74 microliter/min; P less than 0.025) and a reduction in lipid peroxidation (renal malondialdehyde: 0.449 +/- 0.06 vs. 0.698 +/- 0.08 mmol/mg prot; P less than 0.05) compared to control animals. Infusion of 50 mg/kg/hr deferoxamine also protected renal function after ischemia (inulin clearance: 624 +/- 116 vs. 285 +/- 90 microliter/min; P less than 0.05) and resulted in less histologic injury. Iron-saturated deferoxamine had no protective effect. Conversely, infusion of the iron complex EDTA-FeCl3 during reperfusion exacerbated postischemic renal dysfunction and lipid peroxidation. Following renal ischemia there was no detectable increase in "free" iron in arterial or renal venous plasma. However, urinary "free" iron increased 10- to 20-fold following reperfusion. Iron chelators which underwent filtration and gained access to this free iron in the urine (free deferoxamine or inulin-conjugated deferoxamine) provided protection, whereas a chelator confined to the vascular space (dextran-conjugated deferoxamine) did not.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of the endothelin receptor antagonist, tezosentan, before or after renal ischemia protects renal function

BACKGROUND: Utilization of organs subjected to ischemia/reperfusion (I/R) injury could expand the donor pool. Endothelin (ET) is implicated in renal I/R injury. Therefore, our study compared the effectiveness of pre- and postischemic administration of the ET receptor antagonist, Tezosentan, in preserving renal function. METHODS: In a rat model, a kidney was subjected to 45 min of ischemia along with a contralateral nephrectomy. After 24 hr of reperfusion, renal function was assessed by serum creatinine (Scr), inulin clearance (glomerular filtration rate; GFR), and histology. ET-1 peptide expression was localized using immunohistochemistry. Three groups were studied: I/R untreated (n=17), I/R pretreated (n=11), and I/R posttreated (n=13) with Tezosentan (15 mg/kg, i.v.). RESULTS: Tezosentan significantly decreased (P<0.05) the rise in Scr from I/R injury (2.0+/-0.4 mg/dl, before and 2.9+/-0.4 mg/dl, after treatment) compared with untreated animals (4.2+/-0.4 mg/dl). GFR was significantly increased (P<0.05) from 0.13+/-0.03 ml/min (untreated animals) to 0.74+/-0.16 and 0.47+/-0.14 ml/min (pre- and posttreated animals). Untreated animals had significant cortical acute tubular necrosis, which was almost completely prevented by pretreatment with Tezosentan and markedly reduced by posttreatment. Increased ET-1 peptide expression was noted in the renal vasculature and in the cortical tubular epithelium of kidneys exposed to I/R. CONCLUSIONS: The purpose of this study was to optimize the function of kidneys exposed to I/R injury. Pretreatment as well as posttreatment with Tezosentan successfully decreased Scr, increased GFR, and maintained renal architecture in kidneys after ischemia. Therefore, ET receptor antagonists may be useful to preserve renal function in the transplantation setting.     

Renal work, glutathione and susceptibility to free radical-mediated postischemic injury

Studies were performed to determine whether renal glutathione (GSH) is an important free-radical scavenger following ischemia and reperfusion, whether alterations in renal transport work affect renal GSH levels, and whether a decrease in renal work decreases susceptibility to postischemic renal injury via the first two effects. Following administration of either intravenous GSH to increase renal GSH or intraperitoneal diethylmaleate to decrease renal GSH, Sprague-Dawley rats underwent 60 minutes of renal ischemia. In animals with high renal GSH following GSH infusion, GFR 24 hours after ischemia was 0.43 +/- 0.08 ml/min compared to 0.15 +/- 0.02 ml/min in saline-infused control animals (P less than 0.01). When renal GSH was decreased by the administration of diethylmaleate postischemic renal dysfunction was accentuated. Twenty-four hours after ischemia GFR was 0.05 +/- 0.02 ml/min in diethylmaleate-treated animals and 0.28 +/- 0.06 ml/min in control animals (P less than 0.005). To test whether a decrease in renal transport work alters renal GSH the filtered load of sodium was reduced by producing unilateral renal artery stenosis. Alternatively, renal work was lessened when sodium reabsorption was interfered with by the infusion of a combination of natriuretic agents. Renal artery stenosis produced a 37% decrease in GFR. Renal GSH was 0.435 +/- 0.089 nmol/mg protein in intact kidneys and 0.804 +/- 0.239 nmol/mg protein in stenotic kidneys (P less than 0.05). The infusion of natriuretic agents produced no change in GFR or renal plasma flow but resulted in a striking elevation in renal GSH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cyclosporine administration on renal hemodynamics in conscious rats

The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cyclosporin A on renal function and kidney growth in the uninephrectomized rat

This study was designed to characterize the effect of cyclosporin A (CsA) on renal function and compensatory kidney growth in a rat model of uninephrectomy (Ux). The infusion of CsA (12.5 mg/k body wt) after acute Ux resulted in a fall in glomerular filtration rate (GFR) and renal plasma flow (RPF) and a marked increase in renal vascular resistance (RVR). Three weeks following Ux, GFR was also reduced in CsA treated animals as compared to pair-fed controls (0.39 +/- 0.03 vs. 0.67 +/- 0.06 ml/min/100 g, P less than 0.001), but RPF was not (1.97 +/- 0.14 vs 2.19 +/- 0.34 ml/min/100 g). The reduction in GFR seen in rats treated with CsA was fully reversible two weeks after discontinuation of the drug. Three weeks after Ux, kidney weight in CsA-treated animals increased to the level of pair-fed controls (1.50 +/- 0.05 vs. 1.57 +/- 0.06 g) but renal cortical RNA (39.4 +/- 4.3 vs. 49.3 +/- 1.3 micrograms/ml, P less than 0.05), DNA (26.4 +/- 1.7 vs. 34.7 +/- 2.1 micrograms/ml, P less than 0.01), and protein content (6.4 +/- 0.3 vs. 7.8 +/- 0.2 mg/dl, P less than 0.001) were all markedly reduced. Unilateral renal denervation in CsA-treated rats resulted in an increase in GFR and RPF as compared to that of pair-fed sham-denervated animals also treated with CsA (0.57 +/- 0.06 vs. 0.39 +/- 0.03 ml/min/100 g, P less than 0.025 and 2.14 +/- 0.14 vs. 1.63 +/- 0.20 ml/min/100 g, P less than 0.025, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary PGE2 in rats with chronic partial unilateral ureteral obstruction

Urinary prostaglandin E2 (PGE2) was measured in Munich-Wistar rats with surgically created chronic partial unilateral ureteral obstruction (UUO). Mean values of bladder urine PGE2 were higher in sham than in UUO (24.5 +/- 14.4 vs 12.9 +/- 8.2 ng/mg creatinine, respectively, P less than 0.05). Following diuresis, both ureters were cannulated and urine was collected. PGE2 excretion was increased in sham (66.5 +/- 34.4 and 70.1 +/- 44.5 ng/mg creatinine, left and right, respectively). But in UUO, the obstructed kidney excreted less PGE2 than the contralateral kidney (32.1 +/- 6.0 vs 62.3 +/- 40.4 ng/mg creatinine, obstructed vs contralateral, respectively, P = 0.08). PGE2 synthesis was then determined in separated renal medullary and cortical slices. Renal medullary slices from kidneys with severe obstruction synthesized less PGE2 than the contralateral unobstructed side (3.30 +/- 1.22 vs 10.52 +/- 3.23 ng/mg wet wt-30 min, respectively, P less than 0.05) and failed to respond to arachidonic acid stimulation with any significant increase in PGE2 synthesis (3.30 +/- 1.22 vs 4.47 +/- 1.04 ng/mg wet wt-30 min, baseline vs stimulated). In contrast, contralateral unobstructed kidney slices responded with a significant increase in PGE2 synthesis (10.52 +/- 3.23 vs 21.10 +/- 2.50 ng/mg wet wt-30 min, baseline vs stimulated, P less than 0.05). We conclude that chronic partial UUO in the Munich-Wistar rats resulted in significantly less PGE2 elaboration.     

Effect of a high-protein meal on blood flow to transplanted human kidneys

Renal blood flow in normal adults increases after protein ingestion. The mechanisms that create this hyperperfusion are unclear. A neurogenic factor in humans has not been definitively ruled out. Accordingly, we tested the hypothesis that a high-protein meal significantly increases renal blood flow to the denervated human kidney. We studied 11 transplant recipients (TR) with denervated kidneys and 4 kidney donors (KD) with a single innervated kidney. All subjects had normal urinalysis. Using noninvasive Doppler flowmetry that was previously validated, we determined renal blood flow (RQ, ml/min) after a 12-hr fast (F) and 1, 2, and 3 hr after a high-protein meal (500 ml) of 150 g protein, 30 g fat, and 30 g carbohydrate. The RQ (mean +/- SD, ml/min) at fasting and at 1, 2, and 3 hr postprandially was 409 +/- 100, 446 +/- 100, 493 +/- 122 (P less than 0.05 vs. F), and 500 +/- 123 (P less than 0.05 vs. F), respectively, for the TR, and was 654 +/- 60 (P less than 0.05 vs. TR), 667 +/- 86 (P less than 0.05 vs. TR), 776 +/- 80 (P less than 0.05 vs. F and TR), and 809 +/- 81 (P less than 0.05 vs. F and TR) for KD. We conclude that RQ in TR increases significantly after protein ingestion. Thus, in the noninstrumented, unanesthetized human with a transplanted kidney, neural control is not a factor in the increase in renal blood flow after a high protein meal.     

Clinical benefit of enzyme replacement therapy in Fabry disease

Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (r-halphaGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-Alpha-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23 +/- 8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n = 16; GFR 71 +/- 17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60 +/- 23 ml/min/1.73 m2 (P = 0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0 +/- 2.1 vs 13.4 +/- 2.3 mm). In contrast, patients without impairment of renal function (n = 9) had a more favorable outcome (no clinical events; GFR 115 +/- 18 vs 102 +/- 14 ml/min/1.73 m2, NS; PWT 11.7 +/- 1 and 10.7+/-0.7 mm, P = 0.04). Proteinuria remained unchanged (1.34 +/- 0.94 vs 1.01 +/- 0.97 g/day, n = 10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT.     

Renal preservation after warm ischemia using oxygen free radical scavengers to prevent reperfusion injury

Oxygen free radicals damage kidneys and accumulate during the period of preservation prior to transplantation. We hypothesized that a perfusate containing either an oxygen free radical scavenger such as ceruloplasmin, or an iron-chelating agent such as deferoxamine, would improve kidney preservation. Thirty-eight mongrel dogs underwent autotransplantation of the left kidney after 30 min of warm ischemia and 48 hr of machine perfusion (MOX-100, Water Instruments, Rochester, MN) at 5 degrees C and pH of 7.4. The right kidney was removed at the time of autotransplantation. Four blind code-labeled preservation solutions were tested. SGF-I was used for the control group (Group 1, n = 13), and the remaining animals were transplanted with kidneys preserved with one of three solutions modified from the basic SGF-I solution: Group 2, SGF-I plus deferoxamine (656 mg/liter), n = 8; Group 3, SGF-I ceruloplasmin enriched (72 mg/dl), n = 8; and Group 4, SGF-I ceruloplasmin reduced (3.4 mg/dl), n = 9. Serum creatinine levels were measured daily for 2 weeks and survival curves for each of the four groups were estimated by the Kaplan-Meier method. Peak mean serum creatinine levels +/- standard errors in Groups 1 through 4 were 12.6 +/- 1.97, 7.8 +/- 0.90, 7.1 +/- 1.26, and 8.2 +/- 1.09, respectively. Repeated measures analysis of variance showed statistically significant differences between the groups with respect to their serum creatinine profiles (Wald's test x2 with 3 df = 22.39, P value less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Amino acids protects against renal ischemia-reperfusion injury and attenuates renal endothelin.1 disorder in rats

To investigate nephroprotective effects ofa mixture of 8 L-amino acids on renal ischemia-reperfusioninjury and its effects on renal endothelin-1 (ET-1).